Extracellular Sphingomyelinase Rv0888 of Mycobacterium tuberculosis Contributes to Pathological Lung Injury of Mycobacterium smegmatis in Mice via Inducing Formation of Neutrophil Extracellular Traps.
Extracellular Sphingomyelinase Rv0888 of Mycobacterium tuberculosis Contributes to Pathological Lung Injury of Mycobacterium smegmatis in Mice via Inducing Formation of Neutrophil Extracellular Traps.
复制标题
DOI：
10.3389/fimmu.2018.00677
复制
发表时间：
2018
影响因子：
7.3
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
Dang G;Cui Y;Wang L;Li T;Cui Z;Song N;Chen L;Pang H;Liu S
结核分枝杆菌是结核病的病原体，主要引起肺损伤和结节。虽然巨噬细胞通常被认为是结核分枝杆菌的主要细胞，但新的证据表明，中性粒细胞会迅速招募到受感染的肺中。结核分枝杆菌本身或其早期分泌的抗原靶蛋白6(ESAT-6)可诱导中性粒细胞胞外陷阱(Net)的形成。然而，蚊帐捕捉分枝杆菌，但无法杀死它们。Net的形成在分枝杆菌发病机制中的作用尚不清楚。在这里，我们报道了一种新的结核分枝杆菌胞外因子，双功能酶Rv0888，具有核酸酶和鞘磷脂酶活性。Rv0888鞘磷脂酶活性在体外和小鼠肺内均能诱导Net的形成，并能增强耻垢分枝杆菌在小鼠肺内的定植能力。携带Rv0888鞘磷脂酶基因的耻垢分枝杆菌感染小鼠可引起肺组织的病理损伤和炎症反应，这种损伤和炎症主要由Net介导，由Rv0888鞘磷脂酶诱导，相关蛋白(髓过氧化物酶)激活caspase-3。总之，这项研究为分枝杆菌的发病机制提供了新的线索，并揭示了结核病治疗的新靶点。
Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), which mainly causes pulmonary injury and tubercles. Although macrophages are generally considered to harbor the main cells of M. tuberculosis, new evidence suggests that neutrophils are rapidly recruited to the infected lung. M. tuberculosis itself, or its early secreted antigenic target protein 6 (ESAT-6), can induce formation of neutrophil extracellular traps (NETs). However, NETs trap mycobacteria but are unable to kill them. The role of NETs’ formation in the pathogenesis of mycobacteria remains unclear. Here, we report a new M. tuberculosis extracellular factor, bifunctional enzyme Rv0888, with both nuclease and sphingomyelinase activities. Rv0888 sphingomyelinase activity can induce NETs’ formation in vitro and in the lung of the mice and enhance the colonization ability of Mycobacterium smegmatis in the lungs of mice. Mice infected by M. smegmatis harboring Rv0888 sphingomyelinase induced pathological injury and inflammation of the lung, which was mainly mediated by NETs, induced by Rv0888 sphingomyelinase, associated protein (myeloperoxidase) triggered caspase-3. In summary, the study sheds new light on the pathogenesis of mycobacteria and reveals a novel target for TB treatment.